The unique stability, reactivity and biological properties of fluorinated compounds make them useful in many chemical disciplines. Compounds containing an aryl fluoride moiety are common in pharmaceuticals and agrochemicals because the site containing fluorine is stable toward degradation, and this stability improves biological activity.
The conditions typically used to form aryl-fluorine bonds are harsh; thus the fluorine is usually introduced into the arene ring at the beginning of a synthesis or as part of a building block. Improved methods for late-stage aromatic fluorination would be important for diversification in medicinal chemistry. Moreover, methods for aromatic fluorination with simple fluoride sources would be valuable for the preparation of 18F labeled compounds used in PET imaging. Yet, no general method has been reported for the fluorination of aryl halides.
Instead, aryl fluorides have been prepared by the Balz-Schiemann reaction involving the decomposition of aryldiazonium salts (Scheme 1) (Olah, et al., J. Org. Chem., 44:3872 (1979)). The acidic conditions, the toxicity of the reagents, and the potential for explosions limit the synthetic utility of the Balz-Schiemann reaction (Olah, et al., J. Org. Chem., 44:3872 (1979)). Alternatively, aryl fluorides bearing electron-withdrawing groups have been prepared by the halogen exchange (halex) process in which electron deficient aryl chlorides or nitroarenes undergo nucleophilic aromatic substitution with fluoride at high temperatures (Scheme 1) (Adams, et al., Chem. Soc. Rev., 28:225 (1999)). However, this reaction occurs only with substrates that are activated toward nucleophilic attack.
Recently, transition metal complexes have been used to prepare fluoroarenes (Furuya, et al., Nature, 473:470 (2011)). Palladium-catalyzed fluorination of aryl triflates has been reported (Scheme 2) (Watson, et al., Science, 325:1661 (2009)). Although these findings demonstrated that aryl electrophiles can undergo fluorination in the presence of a transition metal catalyst, the formation of a single product occurred only with substrates bearing electron-withdrawing groups (Watson, et al., Science, 325:1661 (2009)). The triflates for this reaction are formed from phenols, and a reagent for the conversion of phenols to aryl fluorides was reported more recently (Tang, et al., J. Am. Chem. Soc., 133:11482 (2011)). Methods for the conversion of aryl stannanes (Furuya, et al., J. Am. Chem. Soc., 131:1662 (2009); and Tang, et al., J. Am. Chem. Soc., 132:12150 (2010)), boronic acids (Furuya, et al., Angew. Chem. Int. Edit., 47:5993 (2008); and Furuya, et al., Org. Lett., 11:2860 (2009)), and silanes (Tang, et al., Tetrahedron, 67:4449 (2011)) to aryl fluorides with silver or palladium and an electrophilic fluoride source also have been published, but the aryl nucleophiles in these reactions are often prepared from the aryl halide, and therefore a method to convert aryl halides to the corresponding aryl fluorides would be more direct than the reactions of main group-aryl reagents.


Casitas et al. have published a method of performing a copper-mediated halide exchange reaction on an aryl halide precursor substituted with a nitrogen-containing macrocyle, having three amine moieties, which chelates the copper. The results achieved by these workers are limited to such chelating precursors. J. Am. Chem. Soc. 2011, 122, 19386-19392.
Accordingly, a reaction that directly fluorinates an aryl precursor to form the corresponding aryl fluoride at low to modest temperatures (e.g., <300° C.) would represent a significant advance in the art of aryl fluorination and the provision of aryl fluorides. Further, such a reaction that does not require the presence of electron withdrawing substituents on the aryl nucleus would also be of value. Surprisingly, the present invention provides such a reaction and compositions of use in carrying out this reaction.